Background

Alpha1-antitrypsin deficiency (AATD) was first described by Laurell and Eriksson in 1963.
[1, 2] Laurell noted the absence of the band of alpha1- protein in 5 of 1500 serum protein electrophoreses (SPEP) submitted to his laboratory in Sweden.
[1] Laurell and Eriksson found that 3 of the 5 of these patients had emphysema at a young age, and that one had a family history of emphysema. Hence, the cardinal clinical features of AATD were established: absence of a protein in the alpha1 region of the SPEP, emphysema with early onset, and a genetic predisposition.
[1]

AATD is a relatively common genetic condition, often undiagnosed. People with AATD are predisposed to obstructive pulmonary disease and liver disease (eg, cirrhosis and hepatocellular carcinoma in children and adults).
[1, 2, 3] AATD is one of the most common inherited disorders among white persons. Its primary manifestation is early-onset panacinar emphysema. About 1-5% of patients with diagnosed chronic obstructive pulmonary disease (COPD) are estimated to have alpha1-antitrypsin deficiency.
[4] Although extremely rare, emphysema in children with AATD has been reported.
[3] The incidence of liver disease increases with age.
[3]

Slowly progressive dyspnea is the primary symptom, though many patients initially have symptoms of cough, sputum production, or wheezing. Treatment involves smoking cessation, preventive vaccinations, bronchodilators, supplemental oxygen when indicated, and physical rehabilitation in a program similar to that designed for patients with smoking-related COPD. In addition, intravenous (IV) augmentation therapy with alpha1-antitrypsin benefits some patients.

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Pathophysiology

Alpha1-antitrypsin deficiency (AATD) is a genetically inherited autosomal-codominant condition with more than 120 alleles identified.
[1, 2] Alpha1-antitrypsin is the prototype member of the serine protease inhibitor (serpin) superfamily of proteins. AATD is caused by mutations in the SERPINA1 gene located in the long arm of chromosome 14.
[1, 2, 5] This genetic defect alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. As a result, serum levels of alpha1-antitrypsin are decreased, leading to low alveolar concentrations, where the alpha1-antitrypsin molecule normally would serve as protection against proteases such neutrophil elastase. The resulting protease excess in alveoli destroys alveolar walls and causes emphysema. Likewise, the accumulation of excess alpha1-antitrypsin in hepatocytes can also lead to destruction of these cells and ultimately, clinical liver disease.

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Etiology

Alpha1-antitrypsin deficiency (AATD) is an uncommon but not rare disease. It is underdiagnosed.
[1, 2] The responsible genetic defect affects 1 in 3000-5000 individuals, making it 1 of the 3 most common lethal genetic diseases among whites. (The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome.) Fortunately, not every individual with AATD develops clinically significant disease.
[2]

The major biochemical activity of the alpha1-antitrypsin molecule is inhibition of several neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G). Therefore, the protein is more accurately termed alpha1-antiprotease. However, most physicians, and virtually all patients, refer to the disease as alpha1-antitrypsin deficiency, and doctors and patients often refer to those who are affected as "alphas."

Hepatocytes synthesize alpha1-antiprotease. After its release from the liver, alpha1-antiprotease circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principal function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particles in the alveoli.

Alpha1-antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction. In patients with the Z allele, the alpha1-antitrypsin produced has a lysine substituted for glutamate. This results in spontaneous polymerization within the endoplasmic reticulum of the hepatocyte, which leads to decreased serum levels of alpha1-antitrypsin and thus a deficiency of peripheral alpha1-antitrypsin.

Additionally, the accumulation of intrahepatic alpha1-antitrypsin is thought to result in apoptosis of hepatocytes. This initially can manifest as laboratory abnormalities, but also can progress to hepatitis, followed by fibrosis and cirrhosis.
[6]

In healthy persons, alpha1-antiprotease serves as a protective screen that prevents alveolar wall destruction. The lungs have a large surface area and are continuously exposed to a high burden of airborne pathogens, which results in a cellular immune response. This is characterized by local release of oxidants and proteases. The presence of alpha1-antiprotease serves to keep these proteases in check and protect the lungs from unregulated protease activity. Individuals with the alpha1-antitrypsin genetic defect do not release alpha1-antiprotease from the liver, and serum and alveolar levels of the protein are low. Consequently, alveoli lack antiprotease protection. The imbalance of proteases-antiproteases in the alveoli leads to unopposed neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema.

Alveolar cell apoptosis may also play an important role in emphysema pathogenesis. Recent evidence suggests that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation.
[7]

Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years, producing an increase in the number of neutrophils (and neutrophil elastase) in the alveolus and inactivating the remaining small amounts of antiprotease.
[1] Other factors that can accelerate the onset or worsen symptoms of disease include infections and exposures to dust and fumes, which can also cause the recruitment of neutrophils to the alveoli.

Other than cigarette smoking, the role of environmental exposures on spirometric decline in patients with alpha1-antitrypsin deficiency has been uncertain. Banauch et al investigated the possible interaction of alpha1-antitrypsin deficiency and short-term massive pollution in New York City Fire Department (FDNY) rescue workers responding to the World Trade Center (WTC) collapse. In the first 4 years after the event, they found significant accelerated declines in spirometry and increased respiratory symptoms. Declines were related to the degree of exposure at the disaster site and to the degree of AATD.
[8] These results support the theory that environmental factors other than cigarette smoke may play a role in the progression of lung disease in alpha1-antitrypsin-deficient patients. However, the size of the study was very small, and care should be taken in generalizing this theory given the unique nature of the WTC disaster. Further studies are needed.

The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. The SERPINA1 (formerly known as Pi) gene responsible for encoding alpha1-antitrypsin is located on chromosome 14 and is highly pleomorphic, with more than 100 allelic variants (denoted by letters).
[1] The variants are classified based on serum levels of alpha1-antitrypsin protein. M alleles are the most common and normal variants. Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.

Nearly 24 variants of the alpha1-antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1-antiprotease (serum levels of 20-53 µmol/L or 150-350 mg/dL).

The most common form of alpha1-antitrypsin deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of alpha1-antitrypsin in these patients are about 3.4-7 µmol/L, 10-15% of normal serum levels. Serum levels greater than 11 µmol/L appear to be protective.
[1, 4] Emphysema develops in most (but not all) individuals with serum levels less than 9 µmol/L.

Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull. The S gene is more frequent among individuals of Spanish or Portuguese descent, whereas the frequency of the Z gene is highest in patients of Northern or Western European descent.

Patients with the PiSZ phenotype have a 20-50% increased likelihood of developing emphysema compared with MM homozygotes. Serum levels of patients with PiSZ alpha1-antitrypsin deficiency are 75-120 mg/dL.

Patients with the null gene for alpha1-antitrypsin will not produce any alpha1-antitrypsin and are high risk for emphysema (100% by the age of 30 years). None with the null gene develop liver disease because of a lack of production, and thus accumulation, of alpha1-antitrypsin in the hepatocytes. The null gene is the least common of the known alleles associated with alpha1-antitrypsin deficiency.

Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease.

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Epidemiology

Frequency

United States

Alpha1-antitrypsin deficiency (AATD) is 1 of the 3 most common lethal genetic diseases among adult white persons, affecting 1 per 3000-5000 individuals. Severe AATD affects an estimated 70,000-100,000 individuals, and approximately 25 million people carry of at least 1 deficient gene. However, less than 10% of severely deficient individuals are currently identified.
[1, 2, 9, 10]

International

AATD has been identified in all populations, but it is most common in individuals of Northern European (1 in 1600) and Iberian descent. Similar rates are found among white persons worldwide, with an estimated 117 million carriers and 3.4 million affected individuals.

Race

White persons constitute an estimated 117 million carriers and 3.4 million affected individuals. Racial groups other than whites are affected less frequently.

Sex

Women and men are affected in equal numbers.

Age

The enzyme deficiency is congenital and has a bimodal distribution with respect to symptoms. It can be seen in neonates as a cause of neonatal jaundice and hepatitis. It can present in infants as cholestatic jaundice and in children as hepatic cirrhosis or liver failure. AATD is also the leading underlying condition requiring liver transplantation in children.

In adults, AATD leads to chronic liver disease in the fifth decade of life. As a cause of emphysema, it is seen in nonsmokers in the fifth decade of life and during the fourth decade of life in smokers.

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Prognosis

The major manifestation of alpha1-antitrypsin deficiency (AATD) in the first two decades of life is liver disease; pulmonary manifestations appear later. Lung function appears to be normal among adolescents with PiZZ compared with a similarly matched group with alpha1-antiprotease levels in the reference range. FVC, FEV1, residual volume, and total lung capacity measurements were not different between the two groups. Lung function begins to decline at some later point. FEV1 decreases in adult PiZZ patients at 51-317 mL per year (estimated decline in healthy patients is 30 mL/y).

In the NIH registry, PiZZ individuals had a 16% likelihood of surviving to age 60 years in contrast to an 85% likelihood for the general US population. Emphysema was the most common cause of death (72%), and chronic liver disease was second (10%). In the NIH registry, of 1129 affected individuals, the mortality rate was approximately 3% per year and the excess mortality was ascribable entirely to lung and liver disease.
[11]

In the Danish registry, the outlook was better, especially for nonindex cases involving nonsmokers. In this group, survival closely approximated that of the healthy Danish population. The Danish registry confirmed the poor outlook for index cases and the additional mortality risk among patients who smoked.

Prognosis is dependent on how patients are identified. Patients found as a result of screening often have a prognosis near that of healthy people. Those identified because of their symptoms face a more limited future. Specific features that portend a poor prognosis include the following:

Mortality/morbidity

Specific morbidity and mortality rates are unknown. Not all patients with homozygous deficiency develop symptomatic emphysema or cirrhosis; however, among those who develop symptomatic disease, the history of having symptoms for several years and being evaluated by multiple physicians before the diagnosis was made is common. At present, the median time between the observation of symptoms and diagnosis is approximately 8 years.
[10] The mortality rate is high in symptomatic patients.

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Patient Education

Several organizations offer patients and family members education, support and opportunities to participate in research.

The Alpha-1 National Association offers a telephone hotline (1-800-4ALPHA-1), a national newsletter (Alpha-1 News), and local support groups that provide information and support for patients, their families, and their caregivers.

In addition, the AlphaNet and the Alpha 1 Foundation, organizations that provide services to patients and a research focus.

Close-up chest radiograph of the right lower zone of a 39-year-old woman with alpha1-antitrypsin deficiency (AATD). Normal lung markings are absent in the costophrenic angle. Some lung markings are present in the pericardiac region, but even these are diminished.

CT scan of the right middle and right lower lobes in a 38-year-old patient with alpha1-antitrypsin deficiency (AATD). Entire middle lobe and much of the lower lobe are emphysematous; normal lung structures have been replaced by abnormal airspaces. Only the posterior portions of the right lower lobe maintain a normal architecture.

Graph outlines alpha1-antitrypsin levels and risk of lung disease for the 5 most common phenotypes of alpha1-antitrypsin deficiency (AATD). Dashed line at 11 mmol/L (80 mg/mL) represents the threshold level below which emphysema is common.

Disclosure: Received research grant from: quintiles, PRA, ICON, Novartis: Adjudication<br/>Received consulting fee from AZ for consulting; Received consulting fee from Glaxo, Myelin, Meda for consulting; Received grant/research funds from Glaxo for independent contractor; Received consulting fee from Merck for consulting; Received honoraria from Annals of Allergy Asthma Immunology for none; Partner received honoraria from ABAI for none. for: Atlantic Health System.

Additional Contributors

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University